Progesterone plays a major role in reproductive health and functioning. Its effects on, for example, the uterus, breast, cervix and hypothalamic-pituitary unit are well established. It also has extra-reproductive activities that are less well studied, such as effects on the brain, the immune system, the vascular endothelial system and on lipid metabolism. Given this wide array of effects, it is apparent that compounds which mimic some of the effects of progesterone (agonists), antagonize these effects (antagonists) or exhibit mixed effects (partial agonists or mixed agonist/antagonist) can be useful in treating a variety of medical conditions.
Information indicating that anti-progestational agents could be effective in a number of medical conditions is available. For example, this information has been summarized in a report from the Institute of Medicine compiled by Donaldson et al., Editors, Clinical Applications of Mifepristone (RU 486) and Other Anti-progestational agents, Committee on Anti-progestational agents: Assessing the Science, Institute of Medicine, National Academy Press, (1993). The following discussion regarding uterine leiomyomata highlights one non-limiting example of such uses.
Uterine leiomyomata (also called leiomyomas or fibroids) are monoclonal, generally benign, smooth muscle tumors of the myometrium, the muscular portion of the uterus composed of smooth muscle and connective tissue. While these tumors are generally benign, they nonetheless can cause a variety of troubling symptoms. For example, uterine leiomyomata can cause pain in the lower back and abdomen, excessive menstrual bleeding (both in terms of volume and length of menstrual periods or bleeding between menses resulting in anemia and fatigue), pressure on the urinary bladder resulting in frequent urination and/or pressure on the rectum causing constipation. Large leiomyomata can press on the ureters (tubes going from the kidneys to the bladder) causing obstruction or blockage of urine which can lead to kidney damage. Uterine leiomyomata also can cause infertility. In some cases, uterine leiomyomata can cause infertility by impairing the uterine lining, blocking the fallopian tubes, or altering the position of the cervix, thus inhibiting sperm from reaching the uterus.
Uterine leiomyomata are common. Some studies suggest that about 20% to about 30% of all women over the age of 30 have leiomyomata, and an estimated 50% to about 75% of African American women have leiomyomata. Fibroids: An Overview of Diagnosis and Treatment, www.womenshealthservices.com (last visited Dec. 12, 2005). Other studies have found that uterine leiomyomata are clinically apparent in about 25% to about 50% of women (Buttram & Reiter, 36 Fertil. Steril. 433-45 (1981)), although careful pathologic examination of the uterus suggests that the prevalence may be as high as about 80%. Cramer & Patel, 94 Am. J. Clin. Pathol. 435-38 (1990).
The severity of symptoms associated with uterine leiomyomata, as well as their prevalence, requires a treatment for this condition. Previously, the only effective treatment for uterine leiomyomata was hysterectomy, an unacceptable treatment option for many women.
Because hysterectomy is an unacceptable treatment option for many women, other procedures have been developed. For example, myomectomy, the surgical removal of leiomyomata from the uterus was developed as an alternative in some cases. Uterine artery embolization has also been developed. In this radiologic procedure, uterine arteries are partially blocked, thus decreasing blood flow to the uterine leiomyomata inhibiting their growth and/or survival.
Myomectomy can be an effective treatment in some patients, however, there are risks associated with it. Some of these risks include scarring and infection. In some cases, scarring after myomectomy can lead to infertility. Studies of the effectiveness of uterine artery embolization have indicated that most subjects have a significant decrease in bleeding symptoms, as well as a reduction in uterine size. However, uterine artery embolization may also have serious consequences including infection, massive uterine bleeding, and uterine necrosis, requiring emergency surgery. Barbieri, 42 Clin. Obstet. Gynecol. 196-205 (1999). Subjects can also experience significant uterine pain, ischemia, and hypoxic changes following embolization. American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin, No. 16 (May 2000). Based on these negative effects, a need for an acceptable treatment option for uterine leiomyomata remains.
Although the mechanisms leading to uterine leiomyomata tumorogenesis are not completely understood, evidence suggests that the development of uterine leiomyomata is ovarian steroid dependent. Murphy et al., 76(2) J. Clin. Endocrinol. 513-517 (2005) and Buttram et al., 36 Fertil. Steril. 433 (1981) which are both incorporated herein by reference. Part of this evidence comes from the findings that uterine leiomyomata contain both estrogen and progesterone receptors (Wilson et al., 55 Obstet. Gynecol. 20-4 (1980); Soules & McCarty 143 Am. J. Obstet. Gynecol. 6-11 (1980)) and that both of these hormones are thought to be involved in tumor formation. See www.womenshealthservices.com, supra. Further, estrogen and growth hormone are thought to act synergistically to stimulate leiomyomata growth as the two are elevated during pregnancy when the growth of leiomyomata is rapid. That progesterone may play a role in uterine leiomyomata growth is suggested by the finding of increased mitotic count in leiomyomata obtained during the secretory phase than in the proliferative phase of the menstrual cycle. Kawaguchi et al. 160 Am. J. Obstet. Gynecol. 637 (1988). Additionally, when the GnRH-agonist and a progesterone were co-administered, the expected regression of leiomyomata size seen with GnRH-agonist alone is not achieved. Friedman et al., 49 Fertil. Steril. 404 (1988); Wilson et al., 55 Obstet. Gynecol. 22 (1980); Soules et al., 143 Am. J. Obstet. Gynecol. 6 (1982). In addition to endogenous hormones, xenoestrogens in the environment (e.g., organochlorine pesticides, pharmacologic compounds) are also of potential concern as these environmental estrogens have been shown to promote the growth of uterine leiomyomata. Uterine Fibroids, www.raysahelian.com/fibroids (last visited Dec. 12, 2005).
Based on the foregoing, the potential for treating uterine leiomyomata by manipulating endogenous hormone levels emerged. One such treatment involves the use of gonadotropin releasing hormone agonists (GnRH agonists such as Lupron®, Synarel® or Zoladex®) which induce a low-estrogen state. Medical Treatment for Fibroids, www.fibroids.net (last visited Dec. 12, 2005). GnRH agonist treatment has been shown to reduce uterine volume by about 50% after about three months of GnRH agonist therapy. Id. GnRH agonist treatment has also been shown to stop menstrual flow (amenorrhea) allowing women with bleeding-induced anemia to significantly increase their iron stores. Id. Unfortunately, cessation of GnRH agonist treatment is followed by a rapid regrowth of uterine leiomyomata and of the uterus to pre-treatment volume. Id. Additionally, because bone health also requires estrogen, long term use of GnRH agonists can significantly decrease bone density and can lead to bone loss or osteoporosis. Id. Currently, therefore, use of GnRH agonists alone for treatment of uterine leiomyomata is usually limited to a short one to three month preoperative course to shrink the uterus to facilitate a surgical procedure or to induce amenorrhea to improve hematologic condition before surgery. Id.
The use of anti-progestational agents as a treatment for uterine leiomyomata has also emerged. Mifepristone (RU-486; also sold by Danco Laboratories, Inc. under the tradename Mifeprex®) is an anti-progestational agent with antiprogesterone and antiglucocorticoid effects that binds to progesterone receptors more competitively than progesterone itself, thus blocking the actions of progesterone. The inhibition of progesterone triggers the shedding of the uterine wall, much like a normal menstruation.
Mifepristone has been shown to produce an equivalent amount of uterine shrinkage and rates of amenorrhea to GnRH agonists. Kettel et al., 60 Fertil. Steril. 642-46 (1993); Murphy et al., 76 J. Clin. Endocrinol. Metab. 513-17 (1993); Murphy et al., 64 Fertil. Steril. 187-90 (1995). Mifepristone has also been shown to reduce uterine leiomyomata size. Eisinger et al., 101(2) Obstet. Gynecol. 243-50 (2003). Thus, clinical studies of mifepristone for the treatment of uterine leiomyomata have suggested that mifepristone can result in symptomatic improvement. These studies, however, have recommended using doses of mifepristone such as 50 mg or 10 mg. Eisinger et al., supra; Murphy et al., supra. One study has confirmed the effectiveness of mifepristone at 5 mg when administered for 6 months. Eisinger et al., supra. While these doses of mifepristone can help to treat uterine leiomyomata, there are problems associated with them. For example, the highest described doses, such as 50 mg, can increase the prevalence and severity of hot flashes, can cause an elevation in hepatic enzymes and in some cases, due to mifepristone's antiglucocorticoid activity can result in deleterious side effects including, without limitation, glucocorticoid deprivation in the tissue and the pituitary gland resulting in an increase in serum ACTH and cortisol, as well as overt symptoms including complaints of anorexia, nausea, dizziness, weakness and somnolence. While the lower described doses, such as 10 mg, can cause less severe drawbacks, these doses can still be associated with side effects such as increased hot flashes, potentially interfering with patient compliance. Therefore, a need exists for a uterine leiomyomata treatment that is not associated with these drawbacks. A need also exist for treatments for other progesterone-related disorders that are not associated with these drawbacks.